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WO2007080598A2 - Composition pharmaceutique pour inhiber/réduire une prolifération et une resténose néointimale - Google Patents

Composition pharmaceutique pour inhiber/réduire une prolifération et une resténose néointimale Download PDF

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Publication number
WO2007080598A2
WO2007080598A2 PCT/IN2006/000008 IN2006000008W WO2007080598A2 WO 2007080598 A2 WO2007080598 A2 WO 2007080598A2 IN 2006000008 W IN2006000008 W IN 2006000008W WO 2007080598 A2 WO2007080598 A2 WO 2007080598A2
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WIPO (PCT)
Prior art keywords
diphenyleneiodonium
restenosis
pharmaceutical composition
combination
inhibiting
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Ceased
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PCT/IN2006/000008
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WO2007080598A3 (fr
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Baskaran Chandrasekar
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Priority to PCT/IN2006/000008 priority Critical patent/WO2007080598A2/fr
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Publication of WO2007080598A3 publication Critical patent/WO2007080598A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/025—Halogenated hydrocarbons carbocyclic
    • A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • a pharmaceutical composition for inhibiting / reducing neointimal proliferation and restenosis is provided.
  • the present invention relates generally to a composition for the prevention of restenosis after percutaneous coronary intervention, and specifically to the inhibition/reduction of neointimal formation following percutaneous coronary intervention by inhibition / reduction of oxidative stress and cell cycle inhibition.
  • Lipid peroxidation may predict restenosis after coronary balloon angioplasty. Jpn Circ J 2001;65:495-9). Oxidative stress after arterial injury is an early event, and is likely to act as an amplifier of the late cellular response (Azevedo LC, et al. Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis. Cardiovasc Res. 2000;47:436 ⁇ 45; Janiszewski M, et al. Oxidized thiols markedly amplify the vascular response to balloon injury in rabbits through a redox active metal-dependent pathway. Cardiovasc Res. 1998;39:327-38).
  • diphenyleneiodonium for inhibiting and reducing reactive oxygen metabolites has been described.
  • the use of diphenyleneiodonium was for inhibiting the oxidative stress associated with several medical conditions where reactive oxygen metabolites were thought to contribute to the disease state.
  • Diphenyleneiodonium was administered by oral, subcutaneous, intravenous, intraperitoneal, or intramuscular injection, by inhalation, or by infusion devices such as syringe pumps, auto injector systems and minipumps, by implantable or injectable polymer matrices, and transdermal formulations.
  • diphenyleneiodonium directly into the arterial wall (intra-mural) has not been described in the art.
  • none of the above patents describe the application of diphenyleneiodonium for the prevention of restenosis following percutaneous coronary intervention. Restenosis is not a disease, but is a complication of the percutaneous coronary intervention procedure.
  • the antiproliferative effect of diphenyleneiodonium could also result from arrest of cell cycle division by inhibition of G(I) and G(2) phases of cell division (Scaife RM. Selective and irreversible cell cycle inhibition by diphenyleneiodonium. MoI Cancer Ther 2005;4:876-84; Scaife RM.
  • Diphenyleneiodonium is a powerful inhibitor of the enzyme NADPH oxidase. In ex-vivo animal experiments, arterial injury resulted in increase of oxidative stress that was inhibited by the presence of diphenyleneiodonium, due to a decrease in NF- kappaB activation (Souza HP, et al. Vascular oxidant stress early after balloon injury: evidence for increased NAD(P)H oxidoreductase activity. Free Radic Biol Med. 2000; 28: 1232-1242). Diphenyleneiodonium inhibits migration of vascular smooth muscle cells by inhibiting activation of p38 MAPK by reactive oxygen species (Wang Z, et al.
  • Diphenyleneiodonium also leads to arrest of cell proliferation by the inhibition of G(I) and G(2) phases of cell division cycle (Scaife RM. Selective and irreversible cell cycle inhibition by diphenyleneiodonium. MoI Cancer Ther 2005;4:876-84; Scaife RM. G2 cell cycle arrest, down-regulation of cyclin B, and induction of mitotic catastrophe by the flavoprotein inhibitor diphenyleneiodonium. MoI Cancer Ther 2004;3: 1229-37). Diabetic patients characteristically exhibit elevated vascular NADPH levels and may particularly benefit from the administration of diphenyleneiodonium during percutaneous coronary intervention.
  • Tetraploidization has been reported with diphenyleneiodonium, a finding that has also been documented with paclitaxel, an inhibitor of cell division that is currently being used in the prevention of restenosis (Chen JG, et al. Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res 2003;63:7891-9; Andreassen PR, et al. Chemical induction of mitotic checkpoint override in mammalian cells results in aneuploidy following a transient tetraploid state. Mutat Res 1996;372: 181-94).
  • diphenyleneiodonium and paclitaxel differ in their differences between diphenyleneiodonium and paclitaxel (Scaife RM. G2 cell cycle arrest, down-regulation of cyclin B, and induction of mitotic catastrophe by the flavoprotein inhibitor diphenyleneiodonium. MoI Cancer Ther 2004;3: 1229-37).
  • diphenyleneiodonium treated cells are arrested in the cell cycle prior to mitosis.
  • diphenyleneiodonium impairs cyclin Bl accumulation, which has not been reported with paclitaxel.
  • paclitaxel unlike diphenyleneiodonium, has not been demonstrated as an inhibitor of oxidative stress.
  • the present invention relates to a pharmaceutical composition for inhibiting / reducing neointimal proliferation and preventing restenosis following percutaneous coronary intervention
  • a pharmaceutical composition for inhibiting / reducing neointimal proliferation and preventing restenosis following percutaneous coronary intervention comprising diphenyleneiodonium and / or its functional equivalents either alone or in combination with one or more pharmaceutically effective compound capable of preventing restenosis said composition capable of being administered locally into the wall of the coronary artery.
  • This invention also provides a method of treating neointimal proliferation and preventing restenosis comprising the step of administering locally into the wall of the coronary artery a pharmaceutical composition containing diphenyleneiodonium and / or its functional equivalents either alone or in combination with one or more pharmaceutically effective compounds capable of preventing restenosis.
  • the present invention further provides a method of administering a pharmaceutically effective dosage of diphenyleneiodonium and / or its functional equivalents either alone or in combination with one or more pharmaceutically effective compounds capable of preventing restenosis locally for inhibiting / reducing neointimal proliferation and restenosis after percutaneous coronary intervention.
  • diphenyleneiodonium may not achieve a local concentration of the agent sufficient to produce a significant effect. Administration of higher systemic doses to produce the desired effect may result in intolerance or adverse effects. Locally delivering diphenyleneiodonium directly into the wall of the coronary artery would eliminate any adverse effects associated with systemic administration. As the diphenyleneiodonium is delivered directly to the desired site of action, the dose required to produce the desired effect is also markedly reduced, further decreasing the incidence of any possible adverse effect.
  • the local delivery of diphenyleneiodonium can be performed at the end of balloon angioplasty procedure with the help of a variety of drug delivery catheters.
  • drug delivery catheters for injection of drugs directly into the wall of a coronary artery is well described and is known to those skilled in the art (Chandrasekar B, et al. Local delivery in coronary artery disease: an overview for the interventional cardiologist. Indian Heart Journal 1999; 51: 21-6.).
  • These include, but are not limited to a double-balloon catheter, porous balloon catheter, infusion sleeve catheter, coil balloon catheter (Dispatch catheter), iontophoretic balloon catheter, the infiltrator, and the hydrogel-coated balloon catheter.
  • an aqueous solution of diphenyleneiodonium (1 ml to 10 ml) may be injected into the wall of the coronary artery using designated drug delivery catheters.
  • the diphenyleneiodonium may be administered in the form of a suspension of bio-degradable, polymer-derived, encapsulated microspheres or nano-spheres carrying the diphenyleneiodonium.
  • the diphenyleneiodonium can be delivered in the form of a viscous material or gel using a hydrogel-coated balloon catheter.
  • the diphenyleneiodonium can be delivered using iontophoresis.
  • diphenyleneiodonium can be delivered locally into the wall of the coronary artery by means of a drug-eluting stent.
  • the drug-eluting stent may be metallic, made of metal alloy, non-metallic, or biodegradable.
  • the diphenyleneiodonium may be released from the drug-eluting stent either with or without the use of polymers or other bio-degradable materials as drug carriers. Alternatively, the diphenyleneiodonium may be released directly from a bare drug-eluting stent.
  • diphenyleneiodonium may be administered by means of any intravascular device (implantable or non-implantable) capable of achieving a sustained local concentration of diphenyleneiodonium in the wall of the coronary arteries.
  • the dose of diphenyleneiodonium intended to be delivered in the present invention varies from 1.0 microgram/kg to 100 microgram/kg. This is well within the toxicity limit of diphenyleneiodonium. In animal studies, systemic doses of diphenyleneiodonium as high as 1000 microgram/kg administered every day for as long as 4 weeks have demonstrated to be safe with no evidence of toxicity (Kono H, et al. Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. Am J Physiol Gastrointest Liver Physiol 2001; 280: G1005-G1012). The dose of diphenyleneiodonium intended to be delivered in the present invention is only a fraction of the dose used for systemic administration in animal studies, and, more importantly, will be administered to the patient only at the time of the percutaneous coronary intervention, and not everyday.
  • Drugs, chemicals, pharmaceutical agents, genetic material and peptides that are functional equivalents of diphenyleneiodonium are included within the scope of this invention.
  • the description of functional equivalence to diphenyleneiodonium will be easily obvious to those skilled in the art.
  • diphenyleneiodonium may inhibit proliferation of human umbilical vein endothelial cells (Balcerczyk A, et al. Induction of apoptosis and modulation of production of reactive oxygen species in human endothelial cells by diphenyleneiodonium. Biochem Pharmacol. 2005 ;69: 1263-73). An adverse effect of diphenyleneiodonium on endothelium has not been demonstrated thus far.
  • diphenyleneiodonium may be administered locally into the wall of the coronary artery in combination with another drug, hormone, chemical, pharmaceutical agent, genetic material, or peptide.
  • Such combinations may include but are not limited to combination of diphenyleneiodonium with one or more of antiproliferative agents, or immunosuppressive agents, or agents that enhance endothelial proliferation and function, hormones such as 17beta- estradiol, anti-inflammatory agents such as dexamethasone, inhibitors of extracellular matrix synthesis, and sulfated polysaccharides (fucoidan, fucoidin, sulfated fucans, etc.), and heparin.
  • the above said combination may either be administered as a single injection, or, as separate injections sequentially.
  • one of the two agents in tihe combination (either diphenyleneiodonium or the second agent) may be administered as an injection and this is followed sequentially by delivery of the other agent in the form of a drug-eluting stent.
  • both the agents (diphenyleneiodonium and the second agent) may be administered loaded onto the same drug-eluting stent.
  • the local delivery of diphenyleneiodonium may also be combined with intravascular brachytherapy.
  • diphenyleneiodonium may be administered locally into the wall of peripheral arteries such as the arteries supplying the limbs, renal arteries or carotid arteries for the inhibition/reduction of neointimal proliferation following percutaneous intervention of these arteries.
  • peripheral arteries such as the arteries supplying the limbs, renal arteries or carotid arteries
  • neointimal proliferation following percutaneous intervention of these arteries.
  • a baseline coronary angiography is performed. Using standard percutaneous coronary intervention equipment, the left anterior descending artery and the right coronary artery of each animal are subjected to balloon angioplasty, and randomized either to drug group or control group. A 3x18 mm stent is deployed in the left anterior descending artery and the right coronary artery of each animal so that one artery receives the drug-eluting stent and the other receives the control stent. Stents are deployed at a 14 atmosphere pressure inflation for 30 seconds, to achieve a stent/artery ratio of 1.2-1.3:1 at full expansion.
  • Coronary angiography After 28 days, the animals are scheduled to undergo coronary angiography. Quantitative coronary , analysis is performed using a computerized edge-detection algorithm. The following coronary artery diameter measurements are made using diastolic frames: (1) basal diameter before injury, (2) diameter at full stent expansion, (3) stent/artery ratio [(2)/(l)], (4) minimal lumen diameter (MLD) of the stented segment at 4 weeks, (5) %-diameter stenosis, and (6) late lumen loss [(2) - (4)].
  • MLD minimal lumen diameter
  • the animals are euthanized.
  • the stented artery segments are harvested and embedded in acrylic plastic and cut into 3 blocks containing the proximal, middle, and distal portions of the stent.
  • Three cross sections are cut from each of these blocks and stained with elastic van Gieson or Movat pentachrome (Heldman AW, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001;103:2289-95). Histomorphometric analysis of the tissue sections is performed by computerized video imaging.
  • the external elastic lamina area (EEL), internal elastic lamina area (IEL) and lumen area are measured, and the %-morphologic stenosis 100 (1 - lumen/IEL area) is calculated.
  • the neointimal thickness (in millimeters) is measured halfway between each pair of strut openings (in-between distance) and averaged over all tissue cross sections. Neointimal thickness is also measured at each strut site (strut-lumen distance) (Heldman AW, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001; 103:2289-95).
  • the degree of re-endothelialization is determined by immunohistochemistry using goat polyclonal anti-mouse platelet/endothelial cell adhesion molecule- 1 (PECAM-I; CD-31) IgG. The lumen circumference and the sum-total of the luminal border staining positively for PECAM-I expression are measured for each section. The degree of reendothelialization is evaluated by the percentage of vascular lumen covered by endothelial cells staining positively for PECAM-I. Inflammation score for each section is obtained by dividing the aggregate of inflammation score around each strut by the total number of struts (Kornowski R, et al.
  • In-stent restenosis contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998;31:224-30). Injury score is determined as previously defined (Schwartz RS, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992;19:267-74).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour inhiber/réduire une prolifération néointimale. La présente composition pharmaceutique comporte du diphényléniodonium et/ou ses équivalents chimiques, seuls ou en combinaison avec tout composé pharmaceutiquement efficace capable d'empêcher une resténose. Cette composition est administrée localement dans la paroi de l'artère coronaire pendant la procédure d'intervention coronaire percutanée.
PCT/IN2006/000008 2006-01-10 2006-01-10 Composition pharmaceutique pour inhiber/réduire une prolifération et une resténose néointimale Ceased WO2007080598A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015039638A1 (fr) 2013-09-20 2015-03-26 Ústav molekulární genetiky AV ČR, v.v.i. Composition pharmaceutique comprenant du diphénylèneiodonium pour traiter des maladies provoquées par les parasites appartenant à la famille destrypanosomatidae

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* Cited by examiner, † Cited by third party
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US4623666A (en) * 1984-11-06 1986-11-18 Kennedy Thomas P Pharmacological applications of diphenylhalonium ion
US6372796B1 (en) * 1996-11-13 2002-04-16 Cold Spring Harbor Laboratory Therapeutic uses for nitric oxide inhibitors
US20020022022A1 (en) * 2000-05-19 2002-02-21 Yi Shi Inhibition of cell proliferation and matrix synthesis by antioxidants and NAD(P)H oxidase inhibitors
AU2003251829B2 (en) * 2002-07-09 2009-12-10 Radical Therapeutix Method to inhibit ischemia and reperfusion injury

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015039638A1 (fr) 2013-09-20 2015-03-26 Ústav molekulární genetiky AV ČR, v.v.i. Composition pharmaceutique comprenant du diphénylèneiodonium pour traiter des maladies provoquées par les parasites appartenant à la famille destrypanosomatidae

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